1. Chapter 18
Ethers and Epoxides;
Thiols and Sulfides

2. Introduction
Ethers are compounds with two organic groups (alkyl, aryl, or vinyl) bonded to the same oxygen atom, R–O–R’, in a ring or in an open chain
industrial solvent
anesthetic perfume solvent

3. Thiols (R–S–H) and sulfides (R–S–R’) are sulfur analogs of alcohols and ethers, respectively
Sulfur replaces oxygen

4. 1. Naming Ethers Ethers are named according to IUPAC rules:
Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether
If other functional groups are present, the ether part is considered an alkoxy substituent

5. Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether

6. If other functional groups are present, the ether part is considered an alkoxy substituent

7. Practice Problem: Name the following ethers according to IUPAC rules
Diisopropyl ether
Cyclopentyl propyl ether
p-Bromoanisole or
4-Bromo-1-methoxybenzene
1-Methoxycyclohexene
Ethyl isobutyl ether
Allyl vinyl ether

8. 2. Structure and Properties of Ethers
The geometry around the O atom of an ether (ROR) is similar to that of water (HOH)
R-O-R has an ~ tetrahedral bond angle (112° in dimethyl ether)
The O atom is sp3-hybridized

9. The oxygen atom gives ethers a slight dipole moment

10. Ethers have higher boiling points than alkanes with similar MW

11. 3. Synthesis of Ethers Ethers can be synthesized by:
Acid-catalyzed dehydration of alcohols
Williamson ether synthesis
Alkoxymercuration of alkenes

12. i. Acid-catalyzed dehydration of alcohols
Symmetrical ethers can be prepared by acid-catalyzed dehydration of primary alcohols (SN2)
Example: Diethyl ether is prepared industrially by sulfuric acid–catalyzed dehydration of ethanol
Acid-catalyzed dehydration of secondary and tertiary alcohols yield alkenes (E1)

13. Practice Problem: Why do you suppose only symmetrical ethers
Practice Problem: Why do you suppose only symmetrical ethers are prepared by the sulfuric acid-catalyzed dehydration procedure? What product(s) would you expect if ethanol and 1-propanol were allowed to react together? In what ratio would the products be formed if the two alcohols were of equal reactivity?

14. ii. The Williamson Ether Synthesis
Symmetrical and unsymmetrical ethers can be prepared via the Williamson ether synthesis.
It is a process in which metal alkoxides react with primary alkyl halides and/or tosylates via SN2
It is the best method for the preparation of ethers

15. Alkoxides are prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH
Acid Base Sodium salt of
the alcohol

16. Silver Oxide-Catalyzed Ether Formation is a variation of the Williamson ether synthesis
Direct reaction of alcohols in Ag2O with alkyl halide forms ether in one step
Example: Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

17. Mechanism of the Williamson Ether Synthesis
The Williamson ether synthesis involves SN2 reaction of an alkoxide ion with a primary alkyl halide
An alkoxide nucleophile (RO-) displaces a halide ion (X-) via SN2
Primary halides and tosylates work best for SN2 because more hindered substrates undergo competitive E2 elimination of HX

18. Unsymmetrical ethers should be synthesized by reaction between the more hindered alkoxide ion and less hindered alkyl halide rather than vice versa
Example: Synthesis of tert-butyl methyl ether

19. Practice Problem: How would you prepare the following ethers
Practice Problem: How would you prepare the following ethers using Williamson synthesis?
Methyl propyl ether
Anisole (methyl phenyl ether)
Benzyl isopropyl ether
Ethyl 2,2-dimethylpropyl ether

20. iii. Alkoxymercuration of Alkenes
Ethers can be prepared via Alkoxymercuration of Alkenes followed by demercuration
Alkoxymercuration occurs when an alkene reacts with an alcohol in mercuric acetate or trifluoroacetate
Demercuration involves reduction of C-Hg by NaBH4

21. Mechanism of Alkoxymercuration/Demercuration
The mechanism involves:
Electrophilic addition of Hg2+ to an alkene, followed by reaction of intermediate cation with alcohol: Overall Markovnikov addition of alcohol to alkene
Reduction of C-Hg by NaBH4

22. Practice Problem: How would you prepare the ethyl phenyl. ether
Practice Problem: How would you prepare the ethyl phenyl ether? Use whichever method you think is more appropriate, the Williamson synthesis
or the alkoxymercuration reaction.

23. Practice Problem: Write the mechanism of the alkoxymercuration
Practice Problem: Write the mechanism of the alkoxymercuration reaction of 1-methylcyclopentene with ethanol Use curved arrows to show the electron flow in each step.

24. alkoxymercuration reaction.
Practice Problem: How would you prepare the following ethers? Use whichever method you think is more appropriate, the Williamson synthesis or the
alkoxymercuration reaction.
Butyl cyclohexyl ether
Benzyl ethyl ether (C6H5CH2OCH2CH3)
sec-Butyl tert-butyl ether
Tetrahydrofuran

25. 3. Reactions of Ethers Ethers undergo: Acidic Cleavage
Claisen Rearrangement

26. i. Acidic Cleavage
Ethers are generally unreactive to most reagents but react with strong acids (HI and HBr) at high temperature
HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1)

27. Mechanism of the Acidic Cleavage
The acidic cleavage reaction takes place:
via SN2 mechanism at the less highly substituted site if only primary and secondary alkyl are bonded to the ether O
via SN1 or E1 mechanism if one of the alkyl groups bonded to the ether O is tertiary

28. Ethers with primary and secondary alkyl groups react with HI or HBr via SN2 mechanism
I- or Br- attacks the protonated ether at the less hindered site

29. Ethers with a tertiary, benzylic, or allylic group react with HI or HBr via SN1 or E1 mechanism
These can produce stable intermediate carbocations
Example: tert-Butyl cyclohexyl ether reacts via E1

30. Practice Problem: Predict the products of the following reaction:
Ethers with primary and secondary alkyl groups – via SN2
Ethers with a tertiary, benzylic, or allylic group – via SN1 or E1

31. Practice Problem: Predict the products of each of the following
Practice Problem: Predict the products of each of the following reactions:

32. Practice Problem: Write the mechanism of the acid-catalyzed
Practice Problem: Write the mechanism of the acid-catalyzed cleavage of tert-butyl cyclohexyl ether to yield cyclohexanol and 2-methylpropene

33. Practice Problem: Why are HI and HBr more effective than HCl
Practice Problem: Why are HI and HBr more effective than HCl in cleaving ethers?
Nucleophilicity usually increases going down a column
of the periodic table
The halide reactivity order is I- > Br- > Cl-

34. ii. Claisen Rearrangement
Claisen rearrangement is specific to allyl aryl ethers, ArOCH2CH=CH2
Heating the allyl aryl ether to 200–250°C leads to an o-allylphenol
Result is alkylation of the phenol in an ortho position

35. Mechanism of the Claisen Rearrangement
The reaction proceeds via a pericyclic mechanism:
a concerted reorganization of bonding electrons involving a 6-electron, 6-membered ring transition state leading to 6-allyl-2,4-cyclohexadienone intermediate
The mechanism is consistent with 14C labelling

36. Practice Problem: What product would you expect from Claisen
Practice Problem: What product would you expect from Claisen rearrangement of 2-butenyl phenyl ether?

37. 4. Cyclic Ethers: Epoxides
Cyclic ether behaves like an acyclic ether, except if the ring is 3-membered
Dioxane and tetrahydrofuran are used as solvents

38. Epoxides (Oxiranes) An epoxide is a three-membered ring ether
It is also called an oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated)
It has a unique chemical reactivity (behaves differently from other open-chain ethers) due to the strain of the 3-membered ring

39. Ethylene oxide (1,2-epoxyethane) is industrially important as an intermediate
It is the simplest epoxide (oxirane)
It is prepared by reaction of ethylene with oxygen at 300°C and silver oxide catalyst

40. In the laboratory, epoxides can be prepared by:
Treatment of an alkene with a peroxyacid
Treatment of a halohydrin with base

41. i. Preparation of Epoxides Using a Peroxyacid
An epoxide is prepared by treatment of an alkene with a peroxyacid (RCO3H)
m-chloroperoxybenzoic acid is a common peroxyacid used

42. The mechanism of epoxidation by treatment of an alkene with a peroxyacid (RCO3H):
is a one-step process in which peroxyacids transfer oxygen to the alkene with syn stereochemistry (no intermediates)

43. ii. Preparation of Epoxides from Halohydrins
An epoxide is prepared by treatment of a halohydrin with base
Addition of HO-X to an alkene gives a halohydrin
Treatment of a halohydrin with base eliminates HX and gives an epoxide

44. The mechanism of epoxidation by treatment of a halohydrin with a base is an intramolecular Williamson ether synthesis:
The nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule

45. Practice Problem: What product would you expect from reaction
Practice Problem: What product would you expect from reaction of cis-2-butene with m-chloroperoxybenzoic acid? Show the stereochemistry

46. Practice Problem: Reaction of trans-2-butene with m-chloropero
Practice Problem: Reaction of trans-2-butene with m-chloropero xybenzoic acid yields an epoxide different from that obtained by reaction of the cis isomer. Explain.

47. 5. Ring-Opening Reactions of Epoxides
There are two types of ring-opening reactions of epoxides:
Acid-Catalyzed Epoxide Opening
Base-Catalyzed Epoxide Opening

48. i. Acid-Catalyzed Epoxide Opening
Water adds to epoxides with dilute acid at room temperature
The product is a 1,2-diol, also called vicinal glycol (on adjacent C’s: vicinal)
Epoxides react under milder conditions because of ring strain

49. Ethylene Glycol
1,2-ethanediol is synthesized from acid catalyzed hydration of ethylene oxide
Widely used as automobile antifreeze (lowers freezing point of water solutions)

50. The mechanism of acid-catalyzed epoxide cleavage involves:
Protonation: Acid protonates oxygen
Backside attack of a nucleophile: water adds to opposite side (trans addition)

51. The mechanism of acid-catalyzed epoxide cleavage is similar to the final step of alkene bromination

52. Halohydrins from Epoxides
Anhydrous HF, HBr, HCl, or HI also combines with an epoxide
This gives a trans product (halohydrin)

53. Regiochemistry of Acid-Catalyzed Opening of Epoxides
When both epoxide carbon atoms are either primary or secondary, the nucleophile preferably attacks the less highly substituted site (less hindered site)
When one of the epoxide carbon atoms is tertiary, the nucleophile attacks the more highly substituted site

54. The mechanism is neither purely SN1 nor SN2.
more stable, tertiary carbocation T.S character (SN1-like)
back-side displacement of leaving group (SN2-like)

55. Practice Problem: Predict the major product of the following reaction:

56. Practice Problem: Predict the major product of each of the
Practice Problem: Predict the major product of each of the following reactions:

57. Practice Problem: How would you prepare the following diols?

58. ii. Base-Catalyzed Epoxide Opening
Unlike other ethers, epoxides can be cleaved by base as well as by acid
Strain of the three-membered ring is relieved on ring-opening
Hydroxide ion cleaves epoxides at elevated temperatures to give trans 1,2-diols

59. Addition of Grignards to Ethylene Oxide
Grignard reagents cleave the ring of epoxides
Reaction of ethylene oxide with Grignard reagent adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain
Acyclic and other larger ring ethers do not react
Grignard reagent

60. Base-catalyzed epoxide opening is SN2-like
Attack of the nucleophile takes place at the less hindered epoxide carbon

61. Practice Problem: Predict the major product of the following
Practice Problem: Predict the major product of the following reactions:

62. 6. Crown Ethers
Crown ethers are large rings consisting of repeating (-OCH2CH2-) or similar units
They were discovered by Charles Pedersen (Dupont; early 1960’s)

63. Crown ethers are named as x-crown-y
x is the total number of atoms in the ring
y is the number of oxygen atoms
Example: 18-crown-6 ether: 18-membered ring containing 6 oxygens atoms
Central cavity is electronegative and attracts cations

64. Uses of Crown Ethers
Complexes between crown ethers and ionic salts are soluble in nonpolar organic solvents
This allows reactions to be carried out under aprotic conditions
It thus creates reagents that are free of water that have useful properties

65. Inorganic salts (eg. KF, KCN, and NaN3) dissolve in organic solvents with the help of crown ethers
This leaves the anion dissociated, enhancing reactivity
Purple benzene

66. Practice Problem: 15-Crown-5 and 12-crown-4 ethers complex
Practice Problem: 15-Crown-5 and 12-crown-4 ethers complex Na+ and Li+, respectively. Make models of these crown ethers, compare the sizes of the cavities.

67. 7. Thiols and Sulfides
Thiols (RSH), also known as mercaptans, are sulfur analogs of alcohols
They are named with the suffix –thiol
SH group is called “mercapto group” (“capturer of mercury”)

68. Sulfides Sulfides (RSR’) are sulfur analogs of ethers
They are named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy

69. Thiols: Formation and Reaction
Thiols are prepared from alkyl halides by SN2 displacement with a sulfur nucleophile such as SH
The alkylthiol product can undergo further reaction with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol

70. Using Thiourea to Form Alkylthiols
For a pure alkylthiol, thiourea (NH2(C=S)NH2) is used as the nucleophile
This gives an intermediate alkylisothiourea salt, which is hydrolyzed cleanly to the alkyl thiourea
This avoids the problem of thiols undergoing further reaction with the alkyl halide to give dialkyl sulfides

71. Oxidation of Thiols to Disulfides
Reaction of an alkylthiol (RSH) with bromine (Br2) or iodine (I2) gives a disulfide (RSSR’)
The thiol is oxidized in the process and the halogen is reduced
It is reversed when the disulfide is reduced back to thiol by treatment with Zn and H+
Disulfide “bridges” form the cross-links between protein chains (stabilize the three dimensional conformations of proteins)

72. Sulfides: Formation and Reaction
Thiolate ions (RS-)
are formed by the reaction of a thiol with a base
react with primary or secondary alkyl halide to give sulfides (RSR’)
are excellent nucleophiles and react with many electrophiles via SN2 mechanism

73. Sulfides as Nucleophiles
Sulfur compounds are more nucleophilic than their oxygen-compound analogs
3p electrons valence electrons (on S) are less tightly held than 2p electrons (on O)
Sulfides react with primary alkyl halides via SN2 to give trialkylsulfonium salts (R3S+)
This is unlike dialkyl ethers

74. Trialkylsulfonium salts are useful alkylating agents:
A nucleophile can attack one of the groups bonded to the positively charged sulfur, displacing a neutral sulfide as leaving group

75. Unlike ethers, sulfides are easily oxidized.
Oxidation of Sulfides
Unlike ethers, sulfides are easily oxidized.
Sulfides are easily oxidized with H2O2 to the sulfoxide (R2SO)
Oxidation of a sulfoxide with a peroxyacid yields a sulfone (R2SO2)

76. Dimethyl sulfoxide (DMSO) is often used as a polar aprotic solvent

77. Practice Problem: Name the following compounds:

78. Practice Problem: 2-Butene-1-thiol is one component of skunk. spray
Practice Problem: 2-Butene-1-thiol is one component of skunk spray. How would you synthesize this substance from methyl 2-butenoate? From ,3-butadiene?

79. 8. Spectroscopy of Ethers
Infrared: C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions.
Proton NMR: H on a C next to ether O are shifted downfield to 3.4  to 4.5 
The 1H NMR spectrum of dipropyl ether shows the these signals at 3.4 
In epoxides, these H’s absorb at  2.5 to  3.5 in their 1H NMR spectra
Carbon NMR: C’s in ethers exhibit a downfield shift to  50 to  80

80. Infrared Spectroscopy
Ethers are difficult to distinguish by IR spectroscopy
C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions.
IR spectrum: CH3CH2OCH2CH3

81. Nuclear Magnetic Resonance Spectroscopy
Proton NMR: H on a C next to ether O are shifted downfield to 3.4  to 4.5 
The 1H NMR spectrum of dipropyl ether shows the these signals at 3.4 

82. Proton NMR: H on a C next to ether O are shifted downfield to 3
Proton NMR: H on a C next to ether O are shifted downfield to 3.4  to 4.5 
In epoxides, these H’s absorb at 2.5 to 3.5  in their 1H NMR spectra
Example: 1,2-epoxypropane

83. Carbon NMR: C’s in ethers exhibit a downfield shift to 50  to 80 
Example: These C’s in methyl propyl ether absorb at 58.5 and 74.8 d
Example: These C’s in anisole absorb at 54.8 d

84. Practice Problem: The 1H NMR spectrum shown is that of an
Practice Problem: The 1H NMR spectrum shown is that of an ether with the formula C4H8O. Propose a structure.

85. Chapter 18
The End